The major histocompatibility complex (MHC) plays key roles in controlling both adaptive and innate immune systems. In the adaptive immune system, both MHC class I and class II antigens recognize, bind and present peptides to cytotoxic and helper T-cells, respectively, and initiate cell-to-cell communication between antigen presenting cells and T-cells by forming immunological synapses and activating both subtypes of T-cells for both cellular and humoral immune systems. In addition, a number of gene clusters in this complex encode proteins which play important roles for antigen processing (proteosome subunit, LMP2 & 7, antigen transporter, TAP1 & 2, antigen loading for class I antigen, Tapasin, antigen loading for class II antigens, DM & DO molecules). In the innate immune system, both classical (HLA-A,-B,-C in human) and non-classical class I (HLA-E) antigens, plus class I-related molecules (MIC-A, -B) interact with natural killer (NK) receptors (KIR & NKG antigens in human and Ly-49 and NKG antigens in mouse) and inhibit and activate NK-cell functions. In addition to the immunological importance, the MHC provides important tools to study molecular evolution. Extremely polymorphic features of both class I and class II antigens identified in most vertebrates provide numerous numbers of peptide binding grooves for MHC class I and II antigens in order to adapt various pathogens. Natural and balancing selections play pivotal roles to generate and maintain these polymorphisms. The nature of multigene clusters of the MHC genes also provides a number of theories to explain the genesis of the MHC. Also, paralogous chromosomal regions found in three other locations in human (chr. 6p21.3 for MHC, 9q33-34, 1, 19 for the others) and jawed vertebrates raises questions for the origin of the MHC. A large-scale sequencing project for the HLA has been launched and completed for the 3.6 Mb of the classical class I, II, & III regions to reveal the molecular history of this important gene complex, and has identified 224 tightly linked genes, including 128 expressed genes, and 96 pseudogenes. More recently, the MHC expands to 4.6 Mb, including five subregions, 1) extended class II (280 kb); 2) class II (700 kb); 3) class III (1000 kb); 4) class I (1600 kb); and 5) extended class I (1000 kb). In contrast of this large complex structure in HLA, the chicken MHC B-locus presents a "minimal essential MHC" disposition extending 92 kb and including 19 functional genes, raising questions about the structure of other MHC systems. The feline MHC has been studied for an approach to comparative gene organization of this multigene cluster in mammals. A 3.1 Mbp sequencing ready BAC/PAC contig map for the feline MHC, including 800 kb extended and classical class II region (HSET to BTLII), 700 kb class III region (Notch 4 to BAT 1) and classical (1,400 kb) and extended (300 kb) class I region (class I gene adjacent to BAT 1 to OLFR) has been completed. The domestic cat MHC has a relatively smaller but a similar class organization as found in human MHC (3.1 Mbp versus 4.6 Mbp, in cat and human MHC, and class order: extended & classical class II, class III, class I and extended class I regions). Sequence work drafts for 17 BAC clones, spanning the entire classical class I region (1,300 kb), from TNF alpha gene to RNF 23 gene have been completed. Twenty-six framework genes, which include TNFA, TNFB, IkBL, ATP6G, BAT1, HNRNPA1, MIClike1, MIClike2, OCT3, SC1, HCR, SPR1, Corneodesmosin (S), VaryltRNA Synthtase, DDR1 kinase, Multispanning Nucleolar Envelope Protein, FLOTILLIN, TUB, KIAA0170, DBP2 PTD017, FB9, ABC50, HSR1, EF1A, RNF23, plus twenty class I genes/gene fragments were identified by GENSCAN and BLASTN/P algorithms. Three class I genes appear to encode classical class I antigens based on predicted amino acid sequences. Comparative analysis between cat and human class I region revealed that although gene contents and orders of framework genes in both MHC systems are very similar, positions of class I gene clusters are unique in each MHCs. The cat MHC lacks class I gene cluster in human HLA-A region. Instead, the cat MHC has 18 class I genes/gene fragments in human HLA-B, -C region, whereas human MHC maintains 4 and 11 class I genes, in HLA-B, -C, and HLA-A region, respectively. Identification of unique gene amplification units, which carries class I gene and BAT1 gene fragment (exon 7,8,9) in cat MHC, suggests convergent origins of class I multigene structure.